The impact of proliferating mast cells in the developing brain

增殖的肥大细胞对发育中的大脑的影响

基本信息

批准号：
10630822
负责人：
Alexa Ciesinski Blanchard
金额：
$ 4.56万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-11 至 2026-04-10
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10630822
关键词：
Address Adolescent Adult Affect Affective Age Attention B-Lymphocytes Behavior Bioinformatics Bone Marrow Brain Cell Count Cell Maintenance Cell Proliferation Cell Shape Cells Central Nervous System Child Childhood Choroid Chronic Clinical Communication Complex Data Development Developmental Process Diagnosis Disease Embryo Fostering Foundations Functional disorder Growth Factor Health Helper-Inducer T-Lymphocyte Heterogeneity Hippocampus Histamine Homeostasis Immersion Immune Immunologist Inflammation Inflammation Mediators Inflammatory Innate Immune System Invaded Life Mediator Mentorship Microglia Molecular Morphology Neurodegenerative Disorders Neurodevelopmental Disorder Neuroglia Neuroimmune Neurologic Deficit Neurologist Neurons Pathology Pattern Pediatric Neurology Perinatal Peripheral Phenotype Physicians Physiological Physiological Processes Population Positioning Attribute Process Proliferating Rattus Regulation Research Role Schizophrenia Scientist Shapes Signal Transduction Site Skin Source Specificity Stimulus Supporting Cell Techniques Testing Thalamic structure Time Tissues Training Vascular Endothelial Growth Factors autism spectrum disorder blood-brain barrier permeabilization brain cell brain tissue career cognitive function cytokine experimental study glial cell development granulocyte hippocampal fissure immune cell infiltrate immunogenic injured insight lateral ventricle mast cell mastocytosis neonatal brain nervous system disorder neural neurodevelopment neurogenesis neuron development novel perinatal period postnatal recruit response single-cell RNA sequencing stem synaptogenesis trafficking transcriptome transcriptomics

项目摘要

Project Summary Both resident and peripheral immune cells are increasingly implicated in the pathophysiology of various neurodevelopmental disorders, including autism, but the mechanisms by which these non-neuronal cells impact the brain is largely unknown. Infiltrating immune cells in the brain readily respond to environmental triggers, promoting persistent proinflammatory signaling that permanently alters developing cells and damages non- renewing populations. The resident immune cells of the brain, microglia, regulate normal physiologic processes to guide brain development, but little is known about the contribution of infiltrating immune cells to these same processes. In my preliminary studies, I found thousands of mast cells, a component of the innate immune system, inhabiting the lateral ventricles adjacent the hippocampus, throughout perinatal stages of brain development. This raises the question – what role might such proinflammatory cells serve in the developing brain? Mast cells (MC) are both highly sensitive to a variety of stimuli and reflexively produce a wide assortment of vasoactive molecules, cytokines, and growth factors, making them a potential neuro-immune hub during neurodevelopment. Moreover, since mast cells are so exquisitely responsive to inflammatory signals, they may serve dual functions: potentially supporting cell genesis and maturation, or perpetrating damage. This proposal seeks to address gaps in our understanding of MC recruitment, heterogeneity, and function in the developing brain to assess how this population may contribute to neurodevelopmental disorders. We have shown, for the first time, that brain MC are replicating along the hippocampal fissure and are maintained in this region for the first two postnatal weeks, paralleling neurogenesis and microglial maturation occurring nearby. Advanced flow cytometric techniques will test the hypothesis that they are locally proliferating, which MC do not typically do outside of the bone marrow (Aim 1.1). To elucidate their functional and molecular identity in the developing CNS, we will perform single cell RNA-sequencing of brain MCs and compare their transcriptome to prototypical MCs from the skin and bone marrow (Aim 1.2). Findings from transcriptomic analyses will guide exploration of their mechanism of influence on typical developmental processes in the hippocampus. Lastly, MC are well known to coordinate with microglia in the injured adult brain, but this relationship has not been thoroughly explored during development. We will test our hypothesis that MCs release signaling factors that promote microglial maturation in the hippocampus (Aim 2). These findings will reframe understanding of the developing brain as an immune-enabled site requiring nuanced neuro-immune interactions to sustain developmental processes. This project fosters training in bioinformatics and immersion in two historically independent fields to prepare me for a career investigating neural-immune communication in health and disease. Scientific mentorship from neuroscientist Dr. Margaret McCarthy and immunologist Dr. Nevil Singh, paralleled by clinical mentorship from neuroimmunologist Dr. David Benavides, will establish a strong foundation for my life as a physician-scientist in the field of child neurology.

项目摘要居民和外周免疫细胞都越来越涉及各种的病理生理学神经发育障碍，包括自闭症，但这些非神经细胞影响的机制大脑在很大程度上未知。浸润大脑中的免疫细胞很容易响应环境触发因素，促进持续的促炎信号传导，该信号永久性地改变了发育中的细胞并损害非 - 更新人口。小胶质细胞的居民免疫细胞调节正常生理过程指导大脑发育，但对浸润免疫细胞的贡献知之甚少过程。在我的初步研究中，我发现了成千上万的肥大细胞，这是先天免疫系统的组成部分，在脑发育的围产期阶段，居住在海马旁边的侧心室。这就提出了一个问题 - 这种促炎细胞在发育中的大脑中有什么作用？肥大细胞（MC）对各种刺激都高度敏感，并且反射性产生各种血管活性分子，细胞因子和生长因子，使它们成为神经发育过程中潜在的神经免疫枢纽。此外，由于肥大细胞对炎症信号的响应非常敏感，因此它们可以发挥双重功能：潜在支持细胞起源和成熟或进行损害。该建议旨在解决空白在我们了解MC招募，异质性和在发育中的大脑中的功能以评估如何人口可能导致神经发育障碍。我们首次表明了大脑MC 沿着海马裂缝进行复制，并在该区域的前两个几周保持在该区域在附近发生的神经发生和小胶质成熟。高级流式细胞仪技术将测试它们在局部增殖的假设，MC通常不会在骨髓之外进行（AIM 1.1）。为了阐明其在发育中的CNS中的功能和分子身份，我们将执行单个细胞脑MC的RNA测序，并将其转录组与皮肤和骨骼的原型MC进行比较骨髓（目标1.2）。转录组分析的发现将指导探索其影响力机理关于海马的典型发育过程。最后，MC众所周知可以与小胶质细胞进行协调在受伤的成年大脑中，但是在开发过程中尚未彻底探索这种关系。我们将测试我们的假设是MC释放促进海马中小胶质成熟的信号传导因子（AIM 2）。这些发现将重新理解发展中的大脑，作为一个支持免疫的网站，需要细微的神经免疫相互作用以维持发展过程。这个项目促进了培训生物信息学和沉浸在两个历史上独立领域，以使我为职业调查做好准备健康和疾病中的神经免疫传播。神经科学家玛格丽特博士的科学心态麦卡锡（McCarthy）和免疫学家尼维尔·辛格（Nevil Singh）博士，与神经免疫学家戴维（David）的临床心态平行贝纳维德斯（Benavides）将为我作为儿童神经病学领域的身体科学家的生活建立坚实的基础。